The ClC family of chloride-conducting ion channels is involved in a host of biological processes; these channels maintain the resting membrane potential in skeletal muscle, modulate excitability in central neurons, and are involved in the homeostasis of pH in a variety of intracellular compartments. Despite their physiological importance, the mechanisms by which these channels function are poorly understood. We are attempting to understand the functional properties of these proteins by examining the function of several family members, including both eukaryotic and prokaryotic homologs. One reason for our limited understanding of this channel family has been the unavailability of high-affinity inhibitors for these channels. For cation channels, the venoms of poisonous animals have been a rich source of peptide toxins which bind-to and inhibit the function of the channels. Investigators have successfully used these toxins to probe the mechanisms and structure-function relationships in these channels. Hoping for similarly useful tools, we have begun a search for ClC inhibitors in a series of venoms. We are currently using various ClC chloride channels expressed in Xenopus oocytes as an assay for the presence of inhibitors. We control for metals, known to inhibit some ClC channels, using channel mutants known to be insensitive to these inhibitors or EDTA which can chelate the metal ions. To date, we have screened approximately 30 venoms against ClC-0 and some of these against ClC-2 as well.